This invention relates to a newly discovered reduction in levels of coenzyme Q.sub.10 in human subjects which is a side effect from the administration of MEVACOR (lovastatin). The reduction of tissue levels of coenzyme Q.sub.10 by oral MEVACOR can in turn cause an increase in cardiac dysfunction, and for patients with advanced cardiac disease, this added dysfunction can be life-threatening. Also, a reduction in levels of CoQ.sub.10 in human subjects by MEVACOR can depress other essential functions in the human body such as the immune function which can also be very clinically serious and even life-threatening, particularly for any cancer patient.
Coronary artery disease is the major cause of death in Western countries. Hypercholesterolemia is known to be a primary risk factor for death from coronary artery disease. It is known that 50% or more of the total body cholesterol in humans is derived from intrinsic biosynthesis. It is also known that a rate-limiting step of major significance in the biosynthesis of cholesterol is at the level of the enzyme known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase or HMG-CoA reductase. This enzyme then was logical for inhibition to reduce the intrinsic biosynthesis of cholesterol toward reducing the risk factor of hypercholesterolemia and coronary artery death.
Alberts et al. (Proc. Natl. Acad. Sci. USA, Vol., 77, No. 7, pp. 3957-3961, July 1980) described the isolation, structure and biochemical properties of an active inhibitor of HGM-CoA reductase which they named mevinolin. The scientific trivial name, mevinolin, introduced in 1980, corresponds to the subsequent trademark name, MEVACOR.RTM., (lovastatin/MSD). This chemical substance is 1,2,6,7,8,8a-hexahydro-.beta.,.delta.-dihydroxy-2,6-dimethyl-8-(2-methyl-1 -oxobutoxy)-1-naphthaleneheptanoic acid.delta.-lactone. The chemical structure of MEVACOR is: ##STR1##
The Product Monograph on MEVACOR by Merck, Sharp and Dohme (issued May 1988, DC 7489503) states that MEVACOR is highly effective in the treatment of hypercholesterolemia. Further, at maximum doses, MEVACOR produced a mean reduction of LDL cholesterol of 39% in two large multicenter control studies. In general, MEVACOR was found to be well-tolerated in continuing extensive clinical trials as based on data from studies worldwide. However, approximately 2% of patients were discontinued from therapy due to drug-related adverse effects in all clinical studies. The most frequently reported adverse experiences were: headache (9.3%), flatus (6.4%), abdominal pain/cramps (5.7%), diarrhea (5.5%) and rash/pruritus (5.2%) (page 66).
Further, (page 66) the adverse experiences on treating patients with MEVACOR in controlled clinical studies were GASTROINTESTINAL (constipation, diarrhea, dyspepsia, flatus, abdominal pain/cramps, heartburn and nausea); and MUSCULOSKELETAL (muscle cramps and myalgia); and NERVOUS SYSTEM/PSYCHIATRIC (dizziness, headache); SKIN (rash/pruritus); and SPECIAL SENSES (blurred vision and dysgeusia). Although some of these adverse experiences were also recorded when a placebo was administered, MEVACOR did produce such adverse experiences without doubt.
Also, (page 67), liver dysfunction from MEVACOR can occur and approximately 0.5% of patients in clinical trials developed a myopathy.
Also, (page 68), there were eye dysfunctions indicated by a high prevalence of baseline lenticular opacities and during clinical trials, the appearance of new opacities was noted. The causal relationship of MEVACOR to these opacities was not established. Of 431 patients, 34 had opacities at the final examination which occurred during 5-15 months after initiating therapy with MEVACOR. However, existing opacities did not appear to increase.
In summary of the tolerability or the side effects from the clinical administration of MEVACOR, this drug does have a variety of definite side effects some of which have justified discontinuation of therapy with MEVACOR, particularly liver dysfunction.